3-cyano, 4-hydroxy-1, 2, 5-thiadiazole, derivatives and process



' pounds, more particularly,

Efihhi Patented Dec. 11, 1962 3,068,238 3-CYANO,4-HYDROXY-1,2,5-THIADIAZGLE, DERlVATiWES AND PRQCESS John Malcolm Rossand William Channing Smith, Wilmington, DeL, assignors to E. 1. du Pontde Ncrnours and Company, Wilmington, DeL, a corporation of Delaware NoDrawing. Filed July 8, 1960, Ser. No. 41,495 7 Ciaims. (Cl. 260-302)This invention relates to a new class of chemical comthis inventionrelates to thiadiazoles and derivatives thereof. This invention furtherrelates to a novel process for the preparation of certain of thethiadiazole compounds.

Various thiadiazole compounds are referred to in the literature as beinguseful as intermediates in the preparation of pharmaceuticals and somehave been asserted to be useful as therapeutic agents themselves. Thepresent invention relates to novel and useful thiadiazole compoundswhich can be readily prepared using inexpensive reactants.

The preparation of 3-cyano-4-hydroxy-1,2,5-thiadiazole and its potassiumsalt can be effected under a wide variety of conditions in which areaction mixture of potassium cyanide and sulphur dioxide is maintainedat temperatures up to 90 C. The thiadiazole compound is easily separatedfrom the reaction mixture in a solvent extraction step in which it iscrystallized from a substantially anhydrous organic solvent. A preferredmethod of preparing the thiadiazole compounds is carried out using anexcess of S under autogenous pressure in the absence of a solventfollowed by the solvent extraction step. Other methods of preparationinclude the reaction of potassium cyanide and sulfur dioxide in thepresence of an organic solvent either under autogenous pressure orsimply in an open vessel. However, in each instance, the practicaloperating temperature is between 25-90 C. and the preferred temperatureis 5075 C. After reaction the thiadiazole compounds are easily separatedfrom the reaction mixture by crystallizing the desired compounds from aconventional organic solvent. The following examples illustrate variousmethods used to prepare the 3-cyano-4-hydroxy-1,2,5-thiadiazole compoundand its potassium salt.

EXAMPLE I Powdered potassium cyanide (227 g.) was charged into a 1-literstainless steel bomb previously purged with nitro gen; the bomb wascooled, evacuated, charged with sulfur dioxide (450 g.; 100% theoreticalexcess), then heated with agitation at 60 C. for 4 hours. Excess sulfurdioxide was bled off from the cooled bomb and the tancolored product(509 g.) removed and powdered through a 12-mesh sieve.

The product was transferred to apparatus and extracted with hotacetonitrile for 16 hours. The hot, colored extract was filtered toremove traces of insoluble inorganic material and carefully concentratedto yield the crystalline thiadiazole, contaminated with a small amountof potassium thiocyanate. Recrystallization from ethanol, involvingdecolorizing with activated charcoal, yielded the pure thiadiazole as a1:1 mixture of the 3-cyano-4-hydroxy compound and its potassium salt(86.3 g.; 51% based on potassium cyanide).

Analysis.-Calcd. for C HN O S K: C, 24.65; H, 0.35; N, 28.75; S, 21.94;K, 13.4%. Found: C, 24.77; H, 0.57; N, 29.09; S, 22.05; K, 13.5%.

Molecular weight (theory 292): Found, 306.

Replacement of acetonitrile as the organic solvent by absolute ethanolyielded 3-cyano-4-hydroxy-1,2,5-thiadi azole in the form of its purepotassium salt, M.P. 307 C.

a Soxhlet extraction Calcd. for C N OSK: C, 21.81; N, 25.44; S, 19.41%.Found: C, 21.29; N, 25.09; S, 19.65%.

Molecular weight (theory 165): Found, 188.

This method is preferred for ease of operation and high yield. Thepreferred solvents are acetonitrile and ethanol. However, many of thecommon organic solvents, such as acetone, allyl alcohol, as well asacetic acid, can also be used. It is necessary that the solvent besubstantially anhydrous to insure maximum yields; once isolated, thethiadiazole compounds are stable in aqueous solution.

As noted above, the preferred temperature is 50-75 C. although up to 90C. is feasible. At temperatures above 90 C. a vigorous exothermicreaction occurs and yields of thiadiazole compounds are considerablyreduced. At temperatures below 25 C. the reaction proceeds so slowly asto be impractical. In an experiment carried out at low temperatures, areaction mixture of potassium cyanide and sulphur dioxide was maintainedat -78 C. for ten days. Although a quantitative reaction occurred,solvent extraction fails to yield the thiadiazole compound or itspotassium salt. Instead, an isomeric product is obtained which willyield the expected thiadiazole derivatives on hydrolysis withhydrochloric acid or sodium hydroxide.

The reaction time decreases rapidly with an increase in the reactiontemperature. For instance, at about 25 C. 100 hours are required for acomplete reaction, and at C. only minutes are necessary.

In addition to the temperature and time factors, complete reaction isdependent on the ratio of KCN:SO Approximately equimolar amounts of KCNand S0 react and it is preferable to employ about 25% excess of S0 forcomplete reaction; KCNzSO ratios up to 1:2 can be used to advantage.

EXAMPLE II A 325 ml. Hastelloy B shaker tube, previously purged withnitrogen, was charged with potassium cyanide (21.5 g.), freshlydistilled acetonitrile (200 ml.) and sulfur dioxide (24 g.). The tubewas shaken and maintained at 75 C. for 2 hours. The slight excesspressure was released from the cooled tube and the finely dividedsuspension of inorganic material was removed from the product byfiltration.

Concentration of the red-colored acetonitrile solution gave acrystalline deposit which was collected and recrystallized from ethanolyielding the pure potassium salt of 3-cyano-4-hyclroxy-1,2,5-thiadiazole(4.85 g.; 27% based on potassium cyanide).

Analysis.Calcd. for C N OSK: C, 21.81; N, 25.44; S, 19.41%. Found: C,22.18, N, 25.32; S, 19.59%.

This method of preparation is less preferred since it requires that thetemperature be closely controlled due to the strongly exothermicreaction. However, the temperature can be advantageously controlledthrough the gradual addition of liquid S0 accompanied by air cooling ofthe reactor. Due to the high solubility of S0 in acetonitrile, it isnecessary to use safety precautions during the discharge of the reactionproduct.

EXAMPLE III A suspension of vacuum dried potassium cyanide (21.3 g.) infreshly distilled acetonitrile (200 ml.) was magnetically stirred in adry flask fitted with condenser and calcium chloride guard tube. Throughthe suspension was bubbled a slow stream of sulfur dioxide dried bypassage through concentrated sulfuric acid and through a tower ofanhydrous calcium sulfate. The temperature of the reaction mixturegradually rose from room temperature to 73 C. and was accompanied by achange in color in the mixture through bright yellow to sandybrown.

The pale-yellow suspended solid was collected and washed withacetonitrile, then ether; it was identified by its infrared spectrum aspredominantly potassium pyrosulfite. The colored filtrate slowlydeposited a mass of pale-yellow needles, these were collected andidentified as the potassium salt of 3-cyano-4-hydroxy-1,2,5-thiadiazole.

Analysis.-Calcd. for C N OSK: C, 21.81; N, 25.44; S, 19.41; K, 23.7%.Found: C, 22.19; N, 26.07; S, 19.58; K, 23.5%.

On standing open to the atmosphere for a further 36 hours, the motherliquor deposited a further mass of crystals which were identified byinfrared as the 1:1 mixture of the cyano-hydroxy compound and itspotassium salt.

The inset acetonitrile in the reaction mixture'is preferred in themethods of Examples 11 and III. The 1:1 mixture can be converted to 100%3-cyano-4-hydroxy- 1,2,5-thiadiazole as follows:

EXAMPLE 1V An aqueous solution of the 1:1 mixture of cyano-hydroxycompound and its potassium salt (78.1 g.) in 750 ml. water wascontinuously extracted with ether for 16 hours. The ether extract wasremoved, dried over sodium sulfate and evaporated under reduced pressureyielding light cream crystals of 3-cyano-4-hydroxy-1,2,5-thiadiazole(31.1 g.; 92% theory) identified by comparison of its infrared spectrumwith an authentic sample.

An aqueous solution of the 1:1 mixture of cyanohydroxy compound and itspotassium salt (61.6 g.) in l-liter water was acidified to pH 2 byaddition of concentrated hydrochloric acid (20 ml.) and continuouslyextracted with ether for 18 hours. The dried ethereal extract wasevaporated to dryness and the cyanohydroxy compound crystallized fromether-benzene (42.3 g.; 80%; M.P. 160-162 C.) identified by infraredcomparison with an authentic sample.

The thiadiazoles made in accordance with the above methods have anoxygen function attached directly to the nucleus. This function offersthe best opportunities for the introduction of other groups, such assulfnydryl, halogen, and other substituents. The oxygen function can bereplaced by a sulfur using phosphorous pentasulfide.

As prepared, the 3-cyano-4-hydroxy compounds can be used asintermediates for various 1,2,5-thiadiazoles. The below examplesillustrate the ease of preparation of these various derivatives.

EXAMPLE V Silver Salt of 3-Cyano-4-hydroxy-1,2,5-Thiadiaz0le A 5%aqueous solution of the thiadiazole potassium salt was treated with aslight excess of aqueous silver nitrate, the fiocculent yellow-whiteprecipitate which formed immediately in quatitative yield was collected,washed with water, ethanol and ether and airdried.

Lithium Salt of 3-Cyan0-4-Hydroxy-1,2,5-Thiadiaz0le An aqueous solutionof 3-cyano-4-hydroxy-1,2,5-thiadiazole was treated at 50 C. with smallportions of powdered lithium carbonate until the pH of the solutionreached 7 and gas evolution ceased. All water was removed under reducedpressure and the resultant soft mass triturated with ether. Colorlessneedles of the lithium salt were collected and washed with ether.

3-Cyano-4-Methoxy-l ,2,5-Thiadiaz0le A suspension ofcyanohydroxythiadiazole silver salt in acetone was heated under refluxwith excess methyl iodide for 12 hours. Evaporation of the filteredreaction product gave a colored residue which separated from ethanol,after charcoal treatment, as colorless rectangular prisms of3-cyano-4-methoxy-1,2,5-thiadiaz0le, M.P. 47- 48 C.

4 3-Hydroxy-1,2,S-Thiadiazole-4-Carboxylic Acid 3-Hydr0xy-I,2,5-Thiadiaz0le-4-Carb0xamide The 1:1 half potassium salt mixture (29.2g.) and 28 g. potassium hydroxide in absolute ethanol (725 ml.) wereheated under reflux for 3.5 hours. The crystalline 15 potassium salt ofthe amide separated during the reaction and was collected from the coldreaction mixture as paleyellow needles (35.5 g.; 96%). Acidification ofan aqueous solution of the salt followed by ether extraction yielded thehydroxyamide, which crystallized from ethanol in deep yellow needles,M.P. 175-177 C.

3-Hydr0xy-1 ,2,5-Thiadiaz0le Sublimed hydroxycarboxylic acid (22.5 g.)was suspended in 50 ml. nitrobenzene, heated under gentle reflux in astream of nitrogen for 2 hours, and allowed to cool. The dark-brownproduct was filtered and the mass of brown crystals (12.5 g.; 80%; M.P.123-127 C.) collected and recrystallized from benzene and benzenepetroleum ether yielding cream-colored needles, M.P.

Many of the compounds of the present invention are useful asstabilizers. They are also useful as intermediates in the preparation ofvarious chemical compounds as coloring agents. In particular,3-cyano-4-hydroxy- 1,2,5-thiadiazole inhibits the polymerization ofacrylonitrile. The potassium salt of the aforementioned thiadiazolecompound when coupled with other compounds is useful as a coloringagent.

A sample of carefully purified, uninhibited acrylonitrile was purgedwith'nitrogen and divided into two portions. To one portion was added 1%by weight of 3-cyano-4-hydroxy-1,2,5-thiadiazole; the other portion wasused as a standard. The samples were exposed to direct sunlight insealed containers. After hours 45 continuous exposure the uninhibitedacrylonitrile became cloudy and considerable amounts of. polymerpreeipitated within a further 3 hours. There were no indications ofpolymerization in the thiadiazole stabilized sample after 150 hourscontinuous exposure.

60 The potassium salt of 3-cyano-4-hydroxy-1,2,5-thiadiazole (1.0 g.)and 5 ml. phosphorus oxychloride were mixed and stirred atroom'temperature for 1 hour, then heated under reflux for 30 minutes.Excess phosphorus oxychloride was removed from the cooled reactionprodnet under reduced pressure and the solid residue ex tracted withbenzene. Test portions of the resultant3-cyano-4-chloro-1,2,5-thiadiazole solution were treated with thefollowing coupling agents producing the listed colors:

(a) N,N-dimethylaniline-orange.

(b) 1,1-bis-(p-dimethylaminophenyl)ethylene purple.

(c) Pyrrole-Z-aldehyde phenylhydrazone-red.

(d) Pyrrole--red.

Throughout the specification parts and percentages are by weight unlessotherwise indicated.

We claim:

1. The method of preparing a thiadiazole compound of the formula whereinX is selected from the group. consisting of H wherein X is selected fromthe group consisting of H and K, comprising reacting potassium cyanidewith an excess of sulfur dioxide at about 2590 C. under autogenouspressure, extracting the reaction mixture so formed with a solventselected from the group consisting of ethanol and acetonitrile, andcrystallizing the thiadiazole compound from the extract obtained.

4. The method of claim 3 wherein the temperature is about 50-75 C.

5. A thiadiazole compound of the formula wherein X is selected from thegroup consisting of hydrogen, lower alkyl and a monovalent metal.

6. 3-cyano-4-hydroxy-1,2,5thiadiazole. 7. The potassium salt of3-cyano-4-hydroxy-1,2,5-thiadiazole.

References Cited in the file of this patent Seel et al.: Chem. Ber.,vol. 88, pages 1747-55 (1955). Khaletskii et al.: Chem. Abstracts, col.4605 (1958).

5. A THIADIAZOLE COMPOUND OF THE FORMULA